In a recent cohort study published in JAMA Network Open, researchers evaluated whether metformin treatment is related to a reduced risk of all-cause dementia in individuals with type 2 diabetes (T2D).

The researchers examined whether mechanisms aside from improved glucose control, corresponding to hemoglobin A1c (HbA1c) levels, mediate this association.

Background

Metformin (dimethylbiguanide) has been the popular first-line treatment for T2D since 2006. Studies have suggested that initiating metformin treatment may reduce dementia risk in those with type 2 diabetes.

Nonetheless, patients continuously terminate metformin treatment for reasons corresponding to gastrointestinal hostile effects and kidney dysfunction. In actual fact, one-fifth of early users use alternative antidiabetic drugs as an alternative of metformin.

In keeping with current recommendations, people should rigorously weigh the advantages versus risks of metformin therapy when the estimated glomerular filtration rate (eGFR) plummets below a certain threshold.

Concerning the study

In the current study, researchers investigated whether cessation of metformin treatment for reasons unrelated to kidney dysfunction (eGFR rates falling below the secure threshold) was related to increased dementia incidence.

They examined electronic health records (EHRs) of a cohort of metformin users enrolled in Kaiser Permanente Northern California (KPNC), considered one of the biggest integrated healthcare delivery systems in the US of America (USA), with over 4.6 million members. 

These individuals were born before January 1, 1955 (older adults), used metformin, weren’t affected by dementia, and accomplished considered one of the 2 health surveys before enrolment into this study.

The follow-up for dementia incidence began with the implementation of their EHRs in 1996 and continued till 2020. They censored participants at age 90, death, dementia diagnosis, or firstly of a 90-day membership gap.

They used the KPNC mortality database to acquire death dates, while data on race and ethnicity were self-reported. Participants self-endorsed as Asians, Blacks, Hispanic/Latino, White, and other or uncertain. KPNC health plan databases confirmed the race and ethnicity of those individuals who didn’t endorse a category.

This cohort study used an emulated trial design, which replicated critical features of an RCT. Accordingly, the team estimated associations analogous to intent-to-treat (ITT) estimates while comparing early metformin terminators with the routine metformin users’ group. 

The team matched early terminators and routine metformin users in a 1:4 ratio. They’d the identical age, gender, and diabetes for a similar duration.

All calculated P values were two-sided, and the statistical threshold of significance for proportional hazard assumptions was set at α = .05. The information was analyzed between November 2021 and September 2023.

Causal mediation evaluation was performed to find out whether changes in HbA1c levels or insulin prescription status mediated the relationships between early metformin termination and all-cause dementia.

Changes in mean HbA1c levels were measured in the course of the 8-16 months post metformin termination and at the identical age amongst matched routine users. For extra analyses, they used changes in insulin prescription status and HbA1c levels measured five years after early metformin termination as mediators.

The researchers conducted mediation analyses using accelerated failure time (AFT) models, which provided a more straightforward interpretation of the observed associations.

Further, they performed Cox proportional regression modeling to find out hazard ratios (HRs) for dementia diagnosis using time since metformin termination because the time scale, stratified by age at metformin treatment initiation and gender. 

The team also conducted sensitivity analyses using creatinine as an alternative of eGFR, with gender-specific cutoffs. In addition they carried out data evaluation restricted to participants with medication adherence of over 80%. 

In further sensitivity analyses, the researchers restricted differences between early and routine users, wherein they discarded differences in HbA1c level of greater than 0.1% and diabetes duration of over one 12 months.

In addition they analyzed data from those early terminators who had initiated metformin throughout the past two years; thus, they showed no diabetes progression.

Results and conclusions

In total, 12,220 early terminators (46.2% women) and 29,126 (46.6% women) routine users, with a mean age of 59.4 and 61.1 years firstly of the primary metformin prescription, respectively, were analyzed.

Early terminators were at 1.21 times higher risk of dementia diagnosis than matched routine users. 

Mediation evaluation revealed that changes in HbA1c level or insulin use contributed to the association between early metformin termination and all-cause dementia, with no contribution for insulin use five years after metformin termination to 0.07 years for HbA1c level at one 12 months after termination, suggesting they minimally mediated the association. The outcomes of sensitivity analyses were just like that of the first evaluation.

Overall, this cohort study of metformin in older adults largely corroborated prior observational research that initiating metformin was related to a reduced risk of dementia. 

Its large sample size and long follow-up period helped the researchers make precise estimates of the association between early metformin termination and all-cause dementia. Furthermore, the study design mitigated the potential for cohort effects and confounding by indication.

This study has necessary implications for the clinical management of diabetes, especially in older adults. 

For people with diabetes at the next risk of dementia, corresponding to carriers of apolipoprotein E (APOE) ε4 allele, mitigating hostile effects slightly than terminating metformin use or using alternative drugs may be simpler.

These patients might consider switching to other metformin formulations (e.g., slower-release metformin) to beat gastrointestinal hostile effects.

Future studies could evaluate the heterogeneity of the observed association of metformin across known risk aspects for dementia. Studies could also extrapolate the study findings to prediabetic groups.